The transcription factor Sox10 is a key regulator of peripheral glial development

Abstract

The molecular mechanisms that determine glial cell fate in the vertebrate nervous system have not been elucidated. Peripheral glial cells differentiate from pluripotent neural crest cells. We show here that the transcription factor Sox10 is a key regulator in differentiation of peripheral glial cells. In mice that carry a spontaneous or a targeted mutation of Sox10, neuronal cells form in dorsal root ganglia, but Schwann cells or satellite cells are not generated. At later developmental stages, this lack of peripheral glial cells results in a severe degeneration of sensory and motor neurons. Moreover, we show that Sox10 controls expression of ErbB3 in neural crest cells. ErbB3 encodes a Neuregulin receptor, and down-regulation of ErbB3 accounts for many changes in development of neural crest cells observed in Sox10 mutant mice. Sox10 also has functions not mediated by ErbB3, for instance in the melanocyte lineage. Phenotypes observed in heterozygous mice that carry a targeted Sox10 null allele reproduce those observed in heterozygous Sox10 Dom mice. Haploinsufficiency of Sox10 can thus cause pigmentation and megacolon defects, which are also observed in Sox10 Dom /+ mice and in patients with Waardenburg-Hirschsprung disease caused by heterozygous SOX10 mutations.

Expression of Sox transcription factors in the developing mouse pancreas

“…Immunodetection with guinea pig anti-insulin (Linco), guinea pig anti-glucagon (Linco), rabbit anti-somatostatin (Dako), rabbit anti-pancreatic polypeptide (Dako), rabbit anti-␤-galactosidase (ICN Pharmaceuticals), and rabbit anti-Pdx1 (kind gift from Helena Edlund) antibodies was performed as described (Sander et al, 2000). As previously detailed, ␤-galactosidase activity was enzymatically detected in heterozygous Sox8- (Sock et al, 2001) and Sox10-deficient mice (Britsch et al, 2001). …”

“…Expression of Sox8 and Sox10 was studied by enzymatic X-gal staining, using mice heterozygous for a gene replacement of the coding sequence with ␤-galactosidase (Britsch et al, 2001;Sock et al, 2001). Sox8 and Sox10 were found in scattered cells at the epithelial/mesenchymal boundary at E10.5 (Fig.…”

“…5E-H), and normal production of amylase (data not shown), suggesting that endocrine and exocrine differentiation does not depend on Sox8 or Sox10 function. In the peripheral nervous system, Sox10 and Sox8 are expressed in glial cells and Sox10 has been shown to be required for the development of these cells (Britsch et al, 2001;Sock et al, 2001). Because pancreatic islets are enveloped in a sheath of glial cells (Teitelman et al, 1998), it is possible that the Sox10-positive cells in the pancreas are indeed glial cells.…”

“…Recently, several Sox genes have been recognized as key players in the regulation of embryonic development and cell fate determination. The analysis of Sox gene mutations in humans, mice, and zebrafish have demonstrated a role for Sox genes in endoderm specification, as well as the development of gonads, lens, heart, lymphocytes, bone, and glial cells (Kent et al, 1996;Schilham et al, 1996;Britsch et al, 2001;Dickmeis et al, 2001;Kamachi et al, 2001;Lefebvre et al, 2001;Stolt et al, 2002). Despite their broad function in embryonic development, the expression and function of Sox genes during development of the pancreas remain to be explored.…”

Significance of the cranial neural crest

“…This integrative role for the neural crest further clarifies the phenotypic alterations seen in several mutant mice in which one or more of the epibranchial ganglia fail to connect to the hindbrain, even though none of the genes in question are expressed in the epibranchial ganglia: Sox-10 (Britsch et al, 2001), COUP-TFI (Qiu et al, 1997b), ErbB4 (Golding et al, 2000), CRKL (Guris et al, 2001), AP-2 (Zhang et al, 1996). It can now be appreciated that these defects are likely to be a secondary consequence of alteration in the behaviour of the neuroglial neural crest cells.…”